Ectoparasite control method

ABSTRACT

This invention relates to a method of controlling or preventing infestations of ectoparasites, preferably hematophageous ectoparasites, on an animal by administering to the animal a composition comprising an parasiticidally effective amount of a compound of Formula 1, or an N-oxide, or a pharmaceutically or veterinarily acceptable salt thereof, 
     
       
         
         
             
             
         
       
     
     wherein
         R 1  is Me, Cl, Br or F;   R 2  is F, Cl, Br, C 1 -C 4  haloalkyl or C 1 -C 4  haloalkoxy;   R 3  is F, Cl or Br;   R 4  is H; C 1 -C 4  alkyl, C 3 -C 4  alkenyl, C 3 -C 4  alkynyl, C 3 -C 5  cycloalkyl, or C 4 -C 6  cycloalkylalkyl, each optionally substituted with one substituent selected from the group consisting of halogen, CN, SMe, S(O)Me, S(O) 2 Me, and OMe;   R 5  is H or Me;   R 6 is H, F or Cl; and   R 7  is H, F or Cl.

FIELD OF THE INVENTION

This invention relates to certain methods for controlling ectoparasiticinsects on homeothermic animals

BACKGROUND OF THE INVENTION

Ectoparasitic insects are particularly bothersome for animals includinghumans. They are annoying as well as possibly harmful due to thepotential transmission of diseases. Although substantial need hasexisted in the industry for products which control or eradicate suchectoparasites, prior art attempts have failed to provide effectiveformulations which are capable of fully eradicating or controlling themwhile also being non-toxic to humans and animals.

In an attempt to meet the consumer demand for products of this nature,various pesticides, insecticides and insect repellant formulations havebeen developed. These products often suffer from drawbacks relating totheir toxicity or lack of efficacy due to evolved resistance of theparasites. There is a pressing need therefore for new chemical compoundsefficacious against such pests which are relatively non-toxic to theanimal species they are used to protect.

SUMMARY OF THE INVENTION

This invention relates to a method of controlling or preventinginfestations of an ectoparasitic insect, preferably a hematophageousectoparasitic insect, on an animal by administering to the animal acomposition comprising an parasiticidally effective amount of a compoundof Formula 1, or an N-oxide, or a salt thereof,

wherein

-   -   R¹ is Me, Cl, Br or F;    -   R² is F, Cl, Br, C₁-C₄ haloalkyl or C₁-C₄ haloalkoxy;    -   R³ is F, Cl or Br;    -   R⁴ is H; C₁-C₄ alkyl, C₃-C₄ alkenyl, C₃-C₄ alkynyl, C₃-C₅        cycloalkyl, or C₄-C₆ cycloalkylalkyl, each optionally        substituted with one substituent selected from the group        consisting of halogen, CN, SMe, S(O)Me, S(O)₂Me, and OMe;    -   R⁵ is H or Me;    -   R⁶is H, F or Cl; and    -   R⁷ is H, F or Cl.

The invention also comprises a compound of Formula 1 for use as amedicament.

The invention also relates to the use of a compound of Formula 1 in themanufacture of a medicament for the treatment of an infestation of anectoparasitic insect on a animal

DETAILS OF THE INVENTION

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having,” “contains” or “containing,” or any othervariation thereof, are intended to cover a non-exclusive inclusion. Forexample, a composition, a mixture, process, method, article, orapparatus that comprises a list of elements is not necessarily limitedto only those elements but may include other elements not expresslylisted or inherent to such composition, mixture, process, method,article, or apparatus. Further, unless expressly stated to the contrary,“or” refers to an inclusive or and not to an exclusive or. For example,a condition A or B is satisfied by any one of the following: A is true(or present) and B is false (or not present), A is false (or notpresent) and B is true (or present), and both A and B are true (orpresent).

Also, the indefinite articles “a” and “an” preceding an element orcomponent of the invention are intended to be nonrestrictive regardingthe number of instances (i.e. occurrences) of the element or component.Therefore “a” or “an” should be read to include one or at least one, andthe singular word form of the element or component also includes theplural unless the number is obviously meant to be singular.

In the above recitations, the term “alkyl”, used either alone or incompound words such as “alkylthio” or “haloalkyl” includesstraight-chain or branched alkyl, such as, methyl, ethyl, n-propyl,i-propyl, or the different butyl isomers. The term “halogen”, eitheralone or in compound words such as “haloalkoxy”, includes fluorine,chlorine, bromine or iodine. Further, when used in compound words suchas “haloalkyl”, or “haloalkoxy”, said alkyl or alkoxy may be partiallyor fully substituted with halogen atoms which may be the same ordifferent. Examples of “haloalkyl” include F₃C, ClCH₂, CF₃CH₂ andCF₃CCl₂. Examples of “haloalkoxy” include CF₃O, HCF₂O, CCl₃CH₂O,HCF₂CH₂CH₂O and CF₃CH₂O.

One skilled in the art will appreciate that not all nitrogen-containingheterocycles can form N-oxides since the nitrogen requires an availablelone pair for oxidation to the oxide; one skilled in the art willrecognize those nitrogen-containing heterocycles which can formN-oxides. One skilled in the art will also recognize that tertiaryamines can form N-oxides. Synthetic methods for the preparation ofN-oxides of heterocycles and tertiary amines are very well known by oneskilled in the art including the oxidation of heterocycles and tertiaryamines with peroxy acids such as peracetic and m-chloroperbenzoic acid(MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butylhydroperoxide, sodium perborate, and dioxiranes such asdimethydioxirane. These methods for the preparation of N-oxides havebeen extensively described and reviewed in the literature, see forexample: T. L. Gilchrist in Comprehensive Organic Synthesis, vol. 7, pp748-750, S. V. Ley, Ed., Pergamon Press; M. Tisler and B. Stanovnik inComprehensive Heterocyclic Chemistry, vol. 3, pp 18-20, A. J. Boultonand A. McKillop, Eds., Pergamon Press; M. R. Grimmett and B. R. T. Keenein Advances in Heterocyclic Chemistry, vol. 43, pp 149-161, A. R.Katritzky, Ed., Academic Press; M. Tisler and B. Stanovnik in Advancesin Heterocyclic Chemistry, vol. 9, pp 285-291, A. R. Katritzky and A. J.Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G.Werstiuk in Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A.R. Katritzky and A. J. Boulton, Eds., Academic Press.

Compounds of this invention can exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. One skilled in the art will appreciate that onestereoisomer may be more active and/or may exhibit beneficial effectswhen enriched relative to the other stereoisomer(s) or when separatedfrom the other stereoisomer(s). Additionally, the skilled artisan knowshow to separate, enrich, and/or to selectively prepare saidstereoisomers. Accordingly, the present invention comprises compoundsselected from Formula 1, N-oxides and salts thereof. Pharmaceutically orveterinarily acceptable salts, suitable to the mode of administration,are contemplated. The compounds of the invention may be present as amixture of stereoisomers, individual stereoisomers, or as an opticallyactive form.

The salts of the compounds of the invention include acid-addition saltswith inorganic or organic acids such as hydrobromic, hydrochloric,nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic,malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic orvaleric acids. In the compositions and methods of this invention, thesalts of the compounds of the invention are preferably acceptable forthe veterinary/pharmaceutical uses described herein.

Of note are compounds of Formula I wherein

-   R⁴ is H or C₁-C₄ alkyl optionally substituted with one substituent    selected from the group consisting of CN, SMe and OMe;-   R⁵ is H or Me;-   R⁶ is H; and-   R⁷ is H.    Of further note are:-   a) Compounds of Formula 1 wherein    -   R¹ is Me or Cl;    -   R² is Cl, Br, CF₃, OCF₂H, OCF₃ or OCH₂CF₃; and    -   R⁴ is H, Me, Et, i-Pr, t-Bu, CH₂CN, CH(Me)CH₂SMe or        C(Me)₂CH₂SMe.-   b) Compounds of a) above wherein    -   R² is Cl, Br, CF₃ or OCH₂CF₃;    -   R⁴ is H, Me, Et or i-Pr; and    -   R⁵is H.-   c) Compounds of b) wherein:    -   R¹ is Me; R² is Br; R³ is Cl; R⁴ is Me.        Of further note are compounds of a, b, c above wherein R⁶ is H;        and R⁷ is H.        A compound of special interest is:

or3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]-phenyl]-1H-pyrazole-5-carboxamide.

The preferred compositions of the present invention are those, whichcomprise the above preferred compounds. The preferred methods of use arethose involving the above-preferred compounds.

“Ectoparasitic insect” means insect ectoparasites of warm bloodedanimals

Hematophagous insect ectoparasites are ectoparasitic insects whichattack their hosts by ingesting blood. By “ingesting” is meant not onlypiercing the animal integument and sucking the blood from thecirculatory system, but also consuming tissue or tissue fluids of thehost and thereby inevitably consume blood or blood constituents.Included within the definition of hematophagous ectoparasitic insectsare fleas, ticks, biting flies, mites, lice, and true bugs.

“Homeothermic Animals” means warm blooded animals. The term is meant toinclude all such animals including humans and particularly importantagronomic or companion animals such cattle, sheep, horses, goats, pigs,llamas, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer,minks, chinchillas, ferrets, racoons, chickens, geese, turkeys, ducks,dogs, cats, mice rats, or the like.

For the purposes of the present invention, the term flea is understoodto refer to all the usual or accidental species of parasitic flea of theorder Siphonaptera. One of the Siphonaptera families known to infestcompanion animals is Pulicidae such as Archaeopsyllinae (cat and dogfleas), Spilopsyllinae (rabbit fleas), or the like.

Of particular interest are the species Ctenocephalides, in particular C.felis and C. canis, rat fleas (Xenopsylla cheopis) and human fleas(Pulex irritans).

For the purposes of this invention the terms ticks and mites are meantto refer the blood-feeding arthropod parasites that belong to the orderAcarina. From the Order Acarina, some of the ticks and mites known toinfest production and companion animals are, Argas spp., Ornithodorosspp., Dermanyssus gallinae, Boophilus spp., Rhipicephalus spp.,Amblyomma spp., Dermacentor spp., Hyalomma spp., Ixodes spp., Psoroptesspp., Chorioptes spp., Sarcoptes spp., Cheyletiella spp., and the like.

There are two well-established families of ticks, the Ixodidae (hardticks), and Argasidae (soft ticks). Ticks often produce injury afterinfestation of animals in three respects: direct damage caused byparasitism such as local injury and blood loss; by toxins injected bythe parasites and by the transmission of diseases. Especially incompanion animals, ticks may be the source of zoonotic diseases.

For the purpose of this invention “lice” (singular: louse), areectoparasites of the order Phthiraptera. Among the Phthiraptera familiesknown to be parasites of animals are: Trichodectidae such as Bovicolabovis (important cattle-biting louse), B. ovis (sheep-biting louse) orB. equi (horsebiting louse); Haematopinidae such as Haematopinus suis(hog louse), or H. asini (horse sucking louse); Linognathidae such asLinognathus stenopsis (goat sucking louse) or L. vituli (long-nosedcattle louse); or the like.

“Flies” are insects in the order Diptera, meaning “two-winged”. Trueflies have one pair of wings used for flying. Posterior to the wings isa pair of stalked knob-like structures (called halteres), which areorgans of balance. Flies undergo complete metamorphosis, i.e. the lifecycle consists of the following stages: egg, larva (called a maggot),pupa, and adult. Each stage of the life cycle may be a target forcontrol and intervention.

Flies may be categorized into two functional categories “biting” and“non-biting” of which biting flies are the primary focus here.

“Biting flies” have specially adapted mouthparts well suited forpiercing the host animal integument. The stable fly Stomoxys calcitransis a good example of a biting fly. The stable fly has a proboscis whichis used to pierce the skin and imbibe blood. Both the males and thefemales are bloodfeeders. The stable fly is often the only biting,blood-sucking fly breeding in any appreciable numbers in and aroundconfined-animal production facilities. Another example of a biting flyis the horn fly, Haematobia irritans irritans, which like the stable flyis a bloodsucker and has great economic impact. Like the stable fly thehorn fly has piercing/sucking mouthparts.

A “parasiticidally effective amount” is the amount of active ingredientneeded to achieve an observable effect diminishing the occurrence oractivity of the target parasite pest. One skilled in the art willappreciate that the parasitically effective dose can vary for thevarious compounds and compositions of the present invention, the desiredparasitical effect and duration, the target invertebrate pest species,the animal to be protected, the mode of application and the like, andthe amount needed to achieve a particular result can be determinedthrough simple experimentation

“Treating” or “Treatment” as it applies to infestation refers to boththe prevention and control of the infestation.

“Parenteral” as a mode of application means taken into the body oradministered in a manner other than through the digestive tract, as byinjection.

“Enteral” as a mode of application means take into the body oradministered through the digestive tract as by oral administration.

Embodiments of the Present Invention Include:

-   Embodiment 1. The method or use described in the Summary of the    Invention wherein the ectoparasitic insect is a hematophageous    ectoparasitic insect-   Embodiment 2 The method or use of as described in the Summary of the    Invention wherein

R¹ is Me or Cl;

R² is Cl, Br, CF₃, OCF₂H, OCF₃ or OCH₂CF₃; and

R⁴ is H, Me, Et, i-Pr, t-Bu, CH₂CN, CH(Me)CH₂SMe or C(Me)₂CH₂SMe.

-   Embodiment 3 The method or use of as described in the Summary of the    Invention wherein

R² is Cl, Br, CF₃ or OCH₂CF₃;

R⁴ is H, Me, Et or i-Pr; and

R⁵ is H.

-   Embodiment 4 The method or use of as described in the Summary of the    Invention wherein the Compound is    3-bromo1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide-   Embodiment 5 The method or use of as described in the Summary of the    Invention or in any of the previous embodiments wherein the    ectoparasite is a hematophageous ectoparasite-   Embodiment 6 The method or use of Embodiment 5 wherein the    hematophagous ectoparasite is selected from the group consisting of    fleas, ticks, lice, mites, and biting flies.-   Embodiment 7 The method or use of any of the previous embodiments    wherein the administering is oral.-   Embodiment 8 The method or of any of the previous embodiments    wherein the administering is parenteral.-   Embodiment 9 The method or use of any of the previous embodiments    wherein the administering is topical.-   Embodiment 10 The method or use of any of the previous embodiments    wherein the animal is a homeothermic animal.-   Embodiment 10a The method or use of Embodiment 10 wherein the animal    is a cat or dog.-   Embodiment 11 The method or use of embodiment 10 wherein the animal    is a herd animal.-   Embodiment 12 The method or use of any of the previous embodiments    wherein the composition comprises at least one additional component    selected from the group consisting of solvents and/or carriers,    emulsifiers and/or dispersing agents.-   Embodiment 13 The method or use of Embodiment 12 wherein the    composition comprises at least one additional biologically active    compound or agent.-   Embodiment 14 The method or use of Embodiment 13 wherein the    additional biologically active compound or agent is selected from    the group consisting of macrocyclic lactones, acetyl cholinesterase    inhibitors, arthropod growth regulators, GABA-gated chloride channel    antagonists, mitochondrial electron transport inhibitors, nicotinic    acetylcholine agonists/antagonists/activator, oxidative    phosphorylation inhibitors, anthelminthics, sodium channel    modulators or other antiparasitic compounds.-   Embodiment 15. The method or use of Embodiment 14 wherein said    biologically active compound is a macrocyclic lactone.-   Embodiment 16 The method or use of Embodiment 14 wherein said    biologically active compound is an acetyl cholinesterase inhibitor    selected from the group of organophosphates and carbamates.-   Embodiment 17 The method or use of Embodiment 14 wherein said    biologically active compound is an arthropod growth regulator    selected from the group of chitin synthesis inhibitors, ecdysone    agonists/disruptors, lipid biosynthesis inhibitor and juvenile    hormone mimics.-   Embodiment 18 The method or use of Embodiment 14 wherein said    biologically active compound is a GABA-gated chloride channel    antagonist.-   Embodiment 19 The method or use of Embodiment 14 wherein said    biologically active compound is a mitochondrial electron transport    inhibitor.-   Embodiment 20 The method or use of Embodiment 14 wherein said    biologically active compound is a nicotinic acetylcholine    agonist/antagonist/activator.-   Embodiment 21 The method or use of Embodiment 14 wherein said    biologically active compound is an oxidative phosphorylation    inhibitor.-   Embodiment 22 The method or use of Embodiment 14 wherein said    biologically active compound is an anthelminthic.-   Embodiment 23 The method or use of Embodiment 14 wherein said    biologically active compound is a sodium channel modulator.

This invention relates to a method of controlling or preventioninfestations of an ectoparasite, preferably a hematophageousectoparasite, on an animal by administering to the animal a compositioncomprising an parasiticidally effective amount of a compound of Formula1, or an N-oxide, or a pharmaceutically or veterinarily acceptable saltthereof,

The compounds of Formula 1 can be used for the protection of an animalfrom an ectoparasitic insect by oral, topical or parenteraladministration of the compound.

Therefore, the invention is understood to include the compounds ofFormula 1 (and compositions containing them) for use as an animalmedicament, or more particularly a ectoparasiticidal animal medicament.The animals to be protected include those delineated in any ofEmbodiments 10, 10a, or 11. The ectoparasitc insect pests include thosedelineated in Embodiments 5 or 6. The medicament may be in oral, topicalor parenteral dosage forms.

The invention is also understood to include the use of compounds ofFormula 1 or any of Embodiments 2, 3, or 4 in the manufacture ofmedicaments for the protection of an animal from a an invertebrateparasitic pest. The animals to be protected include those delineated inany of Embodiments 10, 10a, or 11. The ectoparasitc insect pests includethose delineated in Embodiments 5 or 6. The medicament may be in oral,topical or parenteral dosage forms.

The invention is also understood to include compounds of Formula 1 orany of Embodiments 2, 3, or 4 for use in the manufacture of medicamentsfor the protection of an animal from an invertebrate parasitic pest. Theanimals to be protected include those delineated in any of Embodiments10, 10a, or 11. The ectoparasitc insect pests include those delineatedin Embodiments 5 or 6. The medicament may be in oral, topical orparenteral dosage forms.

The invention is also understood to include compounds of Formula 1 orany of Embodiments 2, 3, or 4 packaged and presented for the protectionof an animal from an invertebrate parasitic pest. The animals to beprotected include those delineated in any of Embodiments 10, 10a, or 11.The ectoparasitc insect pests include those delineated in Embodiments 5or 6. The compounds of the invention may be packaged and presented asoral, topical or parenteral dosage forms.

The invention is also understood to include a process for manufacturinga composition for protecting an animal from an invertebrate parasiticpest characterized in that a compound of Formula 1 is admixed with atleast one pharmaceutically or veterinarily acceptable carrier. Theanimals to be protected include those delineated in any of Embodiments10, 10a, or 11. The ectoparasitc insect pests include those delineatedin Embodiments 5 or 6. The compositions of the invention may be packagedand presented as oral, topical or parenteral dosage forms.

The compounds of Formula 1 which can be used according to the invention,have an excellent action on ectoparasitic insects, particularlyhematophageous ectoparasitic insects. The compounds are uniquely adaptedto enter and and spread through the circulatory of the host whilst beingvery well tolerated by the animal. The invention thus represents agenuine enrichment of the art.

The compounds according to the invention possess a goodectoparasiticidal activity, whilst being of low toxicity to animals. Thecompounds of Formula 1 can be prepared by the methods as described inU.S. Patent Publication 2006/0111403A1 (herein incorporated by referenceto the extent not inconsistent with the disclosure herein) andvariations readily apparent to the skilled artisan.

Synthetic methods for the preparation of N-oxides of heterocycles andtertiary amines are very well known by one skilled in the art includingthe oxidation of heterocycles and tertiary amines with peroxy acids suchas peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide,alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate,and dioxiranes such as dimethydioxirane. These methods for thepreparation of N-oxides have been extensively described and reviewed inthe literature, see for example: T. L. Gilchrist in ComprehensiveOrganic Synthesis, vol. 7, pp 748-750, S. V. Ley, Ed., Pergamon Press;M. Tisler and B. Stanovnik in Comprehensive Heterocyclic Chemistry, vol.3, pp 18-20, A. J. Boulton and A. McKillop, Eds., Pergamon Press; M. R.Grimmett and B. R. T. Keene in Advances in Heterocyclic Chemistry, vol.43, pp 149-161, A. R. Katritzky, Ed., Academic Press; M. Tisler and B.Stanovnik in Advances in Heterocyclic Chemistry, vol. 9, pp 285-291, A.R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H.Cheeseman and E. S. G. Werstiuk in Advances in Heterocyclic Chemistry,vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., AcademicPress.

The following compounds, by way of example and not by limitation, areexpected to be advantageous in the practice of the invention.

TABLE 1

R¹ R² R³ R⁴ R⁵ Me Cl F H H Me Cl F Me H Me Cl F Et H Me Cl F i-Pr H MeCl F t-Bu H Me Cl F CH₂CN H Me Cl F CH(Me)CH₂SMe H Me Cl F C(Me)₂CH₂SMeH Me Cl F Me Me Me Cl Cl H H Me Cl Cl Me H Me Cl Cl Et H Me Cl Cl i-Pr HMe Cl Cl t-Bu H Me Cl Cl CH₂CN H Me Cl Cl CH(Me)CH₂SMe H Me Cl ClC(Me)₂CH₂SMe H Me Cl Cl Me Me Me Cl Br H H Me Cl Br Me H Me Cl Br Et HMe Cl Br i-Pr H Me Cl Br t-Bu H Me Cl Br CH₂CN H Me Cl Br CH(Me)CH₂SMe HMe Cl Br C(Me)₂CH₂SMe H Me Cl Br Me Me Me Br F H H Me Br F Me H Me Br FEt H Me Br F i-Pr H Me Br F t-Bu H Me Br F CH₂CN H Me Br F CH(Me)CH₂SMeH Me Br F C(Me)₂CH₂SMe H Me Br F Me Me Me Br Cl H H Me Br Cl Me H Me BrCl Et H Me Br Cl i-Pr H Me Br Cl t-Bu H Me Br Cl CH₂CN H Me Br ClCH(Me)CH₂SMe H Me Br Cl C(Me)₂CH₂SMe H Me Br Cl Me Me Me Br Br H H Me BrBr Me H Me Br Br Et H Me Br Br i-Pr H Me Br Br t-Bu H Me Br Br CH₂CN HMe Br Br CH(Me)CH₂SMe H Me Br Br C(Me)₂CH₂SMe H Me Br Br Me Me Me CF₃ FH H Me CF₃ F Me H Me CF₃ F Et H Me CF₃ F i-Pr H Me CF₃ F t-Bu H Me CF₃ FCH₂CN H Me CF₃ F CH(Me)CH₂SMe H Me CF₃ F C(Me)₂CH₂SMe H Me CF₃ F Me MeMe CF₃ Cl H H Me CF₃ Cl Me H Me CF₃ Cl Et H Me CF₃ Cl i-Pr H Me CF₃ Clt-Bu H Me CF₃ Cl CH₂CN H Me CF₃ Cl CH(Me)CH₂SMe H Me CF₃ Cl C(Me)₂CH₂SMeH Me CF₃ Cl Me Me Me CF₃ Br H H Me CF₃ Br Me H Me CF₃ Br Et H Me CF₃ Bri-Pr H Me CF₃ Br t-Bu H Me CF₃ Br CH₂CN H Me CF₃ Br CH(Me)CH₂SMe H MeCF₃ Br C(Me)₂CH₂SMe H Me CF₃ Br Me Me Me OCF₂H F H H Me OCF₂H F Me H MeOCF₂H F Et H Me OCF₂H F i-Pr H Me OCF₂H F t-Bu H Me OCF₂H F CH₂CN H MeOCF₂H F CH(Me)CH₂SMe H Me OCF₂H F C(Me)₂CH₂SMe H Me OCF₂H F Me Me MeOCF₂H Cl H H Me OCF₂H Cl Me H Me OCF₂H Cl Et H Me OCF₂H Cl i-Pr H MeOCF₂H Cl t-Bu H Me OCF₂H Cl CH₂CN H Me OCF₂H Cl CH(Me)CH₂SMe H Me OCF₂HCl C(Me)₂CH₂SMe H Me OCF₂H Cl Me Me Me OCF₂H Br H H Me OCF₂H Br Me H MeOCF₂H Br Et H Me OCF₂H Br i-Pr H Me OCF₂H Br t-Bu H Me OCF₂H Br CH₂CN HMe OCF₂H Br CH(Me)CH₂SMe H Me OCF₂H Br C(Me)₂CH₂SMe H Me OCF₂H Br Me MeMe OCH₂CF₃ F H H Me OCH₂CF₃ F Me H Me OCH₂CF₃ F Et H Me OCH₂CF₃ F i-Pr HMe OCH₂CF₃ F t-Bu H Me OCH₂CF₃ F CH₂CN H Me OCH₂CF₃ F CH(Me)CH₂SMe H MeOCH₂CF₃ F C(Me)₂CH₂SMe H Me OCH₂CF₃ F Me Me Me OCH₂CF₃ Cl H H Me OCH₂CF₃Cl Me H Me OCH₂CF₃ Cl Et H Me OCH₂CF₃ Cl i-Pr H Me OCH₂CF₃ Cl t-Bu H MeOCH₂CF₃ Cl CH₂CN H Me OCH₂CF₃ Cl CH(Me)CH₂SMe H Me OCH₂CF₃ ClC(Me)₂CH₂SMe H Me OCH₂CF₃ Cl Me Me Me OCH₂CF₃ Br H H Me OCH₂CF₃ Br Me HMe OCH₂CF₃ Br Et H Me OCH₂CF₃ Br i-Pr H Me OCH₂CF₃ Br t-Bu H Me OCH₂CF₃Br CH₂CN H Me OCH₂CF₃ Br CH(Me)CH₂SMe H Me OCH₂CF₃ Br C(Me)₂CH₂SMe H MeOCH₂CF₃ Br Me Me Me OCF₃ F H H Me OCF₃ F Me H Me OCF₃ F Et H Me OCF₃ Fi-Pr H Me OCF₃ F t-Bu H Me OCF₃ F CH₂CN H Me OCF₃ F CH(Me)CH₂SMe H MeOCF₃ F C(Me)2CH₂SMe H Me OCF₃ F Me Me Me OCF₃ Cl H H Me OCF₃ Cl Me H MeOCF₃ Cl Et H Me OCF₃ Cl i-Pr H Me OCF₃ Cl t-Bu H Me OCF₃ Cl CH₂CN H MeOCF₃ Cl CH(Me)CH₂SMe H Me OCF₃ Cl C(Me)₂CH₂SMe H Me OCF₃ Cl Me Me MeOCF₃ Br H H Me OCF₃ Br Me H Me OCF₃ Br Et H Me OCF₃ Br i-Pr H Me OCF₃ Brt-Bu H Me OCF₃ Br CH₂CN H Me OCF₃ Br CH(Me)CH₂SMe H Me OCF₃ BrC(Me)₂CH₂SMe H Me OCF₃ Br Me Me Cl Cl F H H Cl Cl F Me H Cl Cl F Et H ClCl F i-Pr H Cl Cl F t-Bu H Cl Cl F CH₂CN H Cl Cl F CH(Me)CH₂SMe H Cl ClF C(Me)₂CH₂SMe H Cl Cl F Me Me Cl Cl Cl H H Cl Cl Cl Me H Cl Cl Cl Et HCl Cl Cl i-Pr H Cl Cl Cl t-Bu H Cl Cl Cl CH₂CN H Cl Cl Cl CH(Me)CH₂SMe HCl Cl Cl C(Me)₂CH₂SMe H Cl Cl Cl Me Me Cl Cl Br H H Cl Cl Br Me H Cl ClBr Et H Cl Cl Br i-Pr H Cl Cl Br t-Bu H Cl Cl Br CH₂CN H Cl Cl BrCH(Me)CH₂SMe H Cl Cl Br C(Me)₂CH₂SMe H Cl Cl Br Me Me Cl Br F H H Cl BrF Me H Cl Br F Et H Cl Br F i-Pr H Cl Br F t-Bu H Cl Br F CH₂CN H Cl BrF CH(Me)CH₂SMe H Cl Br F C(Me)₂CH₂SMe H Cl Br F Me Me Cl Br Cl H H Cl BrCl Me H Cl Br Cl Et H Cl Br Cl i-Pr H Cl Br Cl t-Bu H Cl Br Cl CH₂CN HCl Br Cl CH(Me)CH₂SMe H Cl Br Cl C(Me)₂CH₂SMe H Cl Br Cl Me Me Cl Br BrH H Cl Br Br Me H Cl Br Br Et H Cl Br Br i-Pr H Cl Br Br t-Bu H Cl Br BrCH₂CN H Cl Br Br CH(Me)CH₂SMe H Cl Br Br C(Me)₂CH₂SMe H Cl Br Br Me MeCl CF₃ F H H Cl CF₃ F Me H Cl CF₃ F Et H Cl CF₃ F i-Pr H Cl CF₃ F t-Bu HCl CF₃ F CH₂CN H Cl CF₃ F CH(Me)CH₂SMe H Cl CF₃ F C(Me)₂CH₂SMe H Cl CF₃F Me Me Cl CF₃ Cl H H Cl CF₃ Cl Me H Cl CF₃ Cl Et H Cl CF₃ Cl i-Pr H ClCF₃ Cl t-Bu H Cl CF₃ Cl CH₂CN H Cl CF₃ Cl CH(Me)CH₂SMe H Cl CF₃ ClC(Me)₂CH₂SMe H Cl CF₃ Cl Me Me Cl CF₃ Br H H Cl CF₃ Br Me H Cl CF₃ Br EtH Cl CF₃ Br i-Pr H Cl CF₃ Br t-Bu H Cl CF₃ Br CH₂CN H Cl CF₃ BrCH(Me)CH₂SMe H Cl CF₃ Br C(Me)₂CH₂SMe H Cl CF₃ Br Me Me Cl OCF₂H F H HCl OCF₂H F Me H Cl OCF₂H F Et H Cl OCF₂H F i-Pr H Cl OCF₂H F t-Bu H ClOCF₂H F CH₂CN H Cl OCF₂H F CH(Me)CH₂SMe H Cl OCF₂H F C(Me)₂CH₂SMe H ClOCF₂H F Me Me Cl OCF₂H Cl H H Cl OCF₂H Cl Me H Cl OCF₂H Cl Et H Cl OCF₂HCl i-Pr H Cl OCF₂H Cl t-Bu H Cl OCF₂H Cl CH₂CN H Cl OCF₂H ClCH(Me)CH₂SMe H Cl OCF₂H Cl C(Me)₂CH₂SMe H Cl OCF₂H Cl Me Me Cl OCF₂H BrH H Cl OCF₂H Br Me H Cl OCF₂H Br Et H Cl OCF₂H Br i-Pr H Cl OCF₂H Brt-Bu H Cl OCF₂H Br CH₂CN H Cl OCF₂H Br CH(Me)CH₂SMe H Cl OCF₂H BrC(Me)₂CH₂SMe H Cl OCF₂H Br Me Me Cl OCH₂CF₃ F H H Cl OCH₂CF₃ F Me H ClOCH₂CF₃ F Et H Cl OCH₂CF₃ F i-Pr H Cl OCH₂CF₃ F t-Bu H Cl OCH₂CF₃ FCH₂CN H Cl OCH₂CF₃ F CH(Me)CH₂SMe H Cl OCH₂CF₃ F C(Me)₂CH₂SMe H ClOCH₂CF₃ F Me Me Cl OCH₂CF₃ Cl H H Cl OCH₂CF₃ Cl Me H Cl OCH₂CF₃ Cl Et HCl OCH₂CF₃ Cl i-Pr H Cl OCH₂CF₃ Cl t-Bu H Cl OCH₂CF₃ Cl CH₂CN H ClOCH₂CF₃ Cl CH(Me)CH₂SMe H Cl OCH₂CF₃ Cl C(Me)₂CH₂SMe H Cl OCH₂CF₃ Cl MeMe Cl OCH₂CF₃ Br H H Cl OCH₂CF₃ Br Me H Cl OCH₂CF₃ Br Et H Cl OCH₂CF₃ Bri-Pr H Cl OCH₂CF₃ Br t-Bu H Cl OCH₂CF₃ Br CH₂CN H Cl OCH₂CF₃ BrCH(Me)CH₂SMe H Cl OCH₂CF₃ Br C(Me)₂CH₂SMe H Cl OCH₂CF₃ Br Me Me Cl OCF₃F H H Cl OCF₃ F Me H Cl OCF₃ F Et H Cl OCF₃ F i-Pr H Cl OCF₃ F t-Bu H ClOCF₃ F CH₂CN H Cl OCF₃ F CH(Me)CH₂SMe H Cl OCF₃ F C(Me)2CH₂SMe H Cl OCF₃F Me Me Cl OCF₃ Cl H H Cl OCF₃ Cl Me H Cl OCF₃ Cl Et H Cl OCF₃ Cl i-Pr HCl OCF₃ Cl t-Bu H Cl OCF₃ Cl CH₂CN H Cl OCF₃ Cl CH(Me)CH₂SMe H Cl OCF₃Cl C(Me)₂CH₂SMe H Cl OCF₃ Cl Me Me Cl OCF₃ Br H H Cl OCF₃ Br Me H ClOCF₃ Br Et H Cl OCF₃ Br i-Pr H Cl OCF₃ Br t-Bu H Cl OCF₃ Br CH₂CN H ClOCF₃ Br CH(Me)CH₂SMe H Cl OCF₃ Br C(Me)₂CH₂SMe H Cl OCF₃ Br Me Me

TABLE 2

R¹ R² R³ R⁴ R⁶ Me CF₃ Cl Me F Cl CF₃ Cl Me F Br CF₃ Cl Me F Me Cl Cl MeF Cl Cl Cl Me F Br Cl Cl Me F Me Br Cl Me F Cl Br Cl Me F Br Br Cl Me FMe CF₃ Cl i-Pr F Cl CF₃ Cl i-Pr F Br CF₃ Cl i-Pr F Me Cl Cl i-Pr F Cl ClCl i-Pr F Br Cl Cl i-Pr F Me Br Cl i-Pr F Cl Br Cl i-Pr F Br Br Cl i-PrF Me CF₃ Cl Me Cl Cl CF₃ Cl Me Cl Br CF₃ Cl Me Cl Me Cl Cl Me Cl Cl ClCl Me Cl Br Cl Cl Me Cl Me Br Cl Me Cl Cl Br Cl Me Cl Br Br Cl Me Cl MeCF₃ Cl i-Pr Cl Cl CF₃ Cl i-Pr Cl Br CF₃ Cl i-Pr Cl Me Cl Cl i-Pr Cl ClCl Cl i-Pr Cl Br Cl Cl i-Pr Cl Me Br Cl i-Pr Cl Cl Br Cl i-Pr Cl Br BrCl i-Pr Cl

TABLE 3

R¹ R² R³ R⁴ R⁷ Me CF₃ F Me F Cl CF₃ F Me F Br CF₃ F Me F Me Cl F Me F ClCl F Me F Br Cl F Me F Me Br F Me F Cl Br F Me F Br Br F Me F Me CF₃ Fi-Pr F Cl CF₃ F i-Pr F Br CF₃ F i-Pr F Me Cl F i-Pr F Cl Cl F i-Pr F BrCl F i-Pr F Me Br F i-Pr F Cl Br F i-Pr F Br Br F i-Pr F Me CF₃ Cl Me ClCl CF₃ Cl Me Cl Br CF₃ Cl Me Cl Me Cl Cl Me Cl Cl Cl Cl Me Cl Br Cl ClMe Cl Me Br Cl Me Cl Cl Br Cl Me Cl Br Br Cl Me Cl Me CF₃ Cl i-Pr Cl ClCF₃ Cl i-Pr Cl Br CF₃ Cl i-Pr Cl Me Cl Cl i-Pr Cl Cl Cl Cl i-Pr Cl Br ClCl i-Pr Cl Me Br Cl i-Pr Cl Cl Br Cl i-Pr Cl Br Br Cl i-Pr Cl

The invention described herein relates to a method of controlling orprevention of infestations of flies on an animal by administering to theanimal an insecticidally effective amount of a compound of Formula 1.

Administration of Compounds of the Invention

The compounds of Formula 1 of this invention can be applied tohomeothermic animals in need of treatment or prevention of ectoparasiticinfestation. Particularly contemplated are important agronomic orcompanion animals such cattle, sheep, horses, goats, pigs, llamas,camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, minks,chinchillas, ferrets, racoons, chickens, geese, turkeys, ducks, dogs,cats, mice rats, or the like. Herd animals such as cattle, sheep, goats,horses, donkeys, camels, pigs, reindeer, caribou and buffalo may betreated. Humans may also be treated.

Any of the compounds of the present invention, or a suitable combinationof such compounds, may be administered directly to the animal subjectand/or indirectly by applying it to the local environment in which theanimal dwells (such as bedding, enclosures, or the like). Directadministration includes contacting the skin, fur or feathers of asubject animal with the compounds, or by feeding or injecting thecompounds into the animal.

Topical Administration

When topical administration is required, the administration to theanimal or the environment can be accomplished by way of non limitingexample, by sprays, dusts, pour on treatments and controlled-releasedevices, such as ear tags and tapes, neck collars, ear tags, tail bands,limb bands or halters which comprise compounds or compositionscomprising compounds of Formula 1. In addition to sprays and pour ontreatments, application may be by other forms of topical administration,for example, in the form of immersion or dipping, washing, coating withpowder, or application to a small area of the animal.

Application of the compositions according to the invention to theanimals to be treated is done topically via solutions, emulsions,suspensions, (drenches), powders, and pour-on formulations.

The pour-on or spot-on method consists in applying the compound ofFormula 1 to a specific location of the skin or coat, advantageously tothe neck or backbone of the animal. This takes place e.g. by applying aswab or spray of the pour-on or spot-on formulation to a relativelysmall area of the coat, from where the active substance is dispersedalmost automatically over wide areas of the fur owing to the spreadingnature of the components in the formulation and assisted by the animal'smovements.

Importantly the compounds of Formula 1 may be indirectly applied to ananimal by applying it to the local environment in which the animaldwells (such as bedding, enclosures, or the like). Effective use rateswill range from about 1.0 to 50 mg/square meter but as little as 0.1mg/square meter may be sufficient or as much as 150 mg/square meter maybe required. One skilled in the art can easily determine thebiologically effective amount necessary for the desired level of pestcontrol.

The invention notably provides a process for controlling thehematophageous ectoparasites of small mammals, and in particular catsand dogs, is treated by locally depositing on the skin, preferablylocalized over a small surface area (spot-on application) It ispreferable for the treatment according to the invention to be carriedout every one, two or, three months on cats and dogs.

The compounds of the present invention may be administered in acontrolled release form, e.g., in a subcutaneous slow releaseformulation, or in the form of a controlled release device affixed to ananimal such as a fleacollar. Collars for the controlled release of aninsecticide agent for long term protection against flea infestation in acompanion animal are art-known, and are described, for example, by U.S.Pat. No. 3,852,416, U.S. Pat. No. 4,224,901, U.S. Pat. No. 5,555,848 andU.S. Pat. No. 5,184,573.

Large animals particularly herd animals are efficiently treated by avariety of methods well known in the art.

Whole-animal sprays provide rapid relief from fly pressure. Animalsprays are applied either as a dilute coarse spray, often applied underhigh pressure to soak the skin, or as a fine low-volume, moreconcentrated mist.

Self-applicating devices include back rubber covered with an absorbentmaterial treated with an insecticide-oil solution, or dust bags filledwith an insecticidal dust. Back rubbers and dustbags should be placed ingateways, near water and feed source, and in other areas where animalswill make frequent contact with them.

Controlled-release ear tags and tapes are generally very effective forfly control in certain farm areas.

Pour-on treatments involves the application of an insecticide along thebackline of the animal at a prescribed dosage of topical products. Thepour-on or spot-on method is especially advantageous for use on herdanimals such as cattle, horses, sheep or pigs, in which it is difficultor time-consuming to treat all the animals by more labor intensivemethods of administration.

Oral Administration

Compounds of the present invention can be delivered by ingestion to theanimal to be protected After ingestion by the animal to be protected,parasiticidally effective concentrations of compounds of the inventionin the bloodstream protect the treated animal from blood-sucking pestssuch as fleas, ticks and lice.

Parenteral Administration

The compound of Formula 1 may be administered by parenterally includingby injection. Injections may be intravenous, intramuscular orsubcutaneous.

Compositions of the Invention

The compounds of the invention may be applied or administered alone butare typically formulated into a veterinary or pharmaceuticalcomposition. The compounds are prepared or formulated into compositionsin a known manner, for example by extending the active compounds withsolvents and/or carriers, if appropriate using emulsifiers and/ordispersing agents; if, for example, water is used as the diluent,organic solvents can, if appropriate, be used as auxiliary solvents.

Typically a parasiticidal composition according to the present inventioncomprises a mixture of a compound of Formula 1 with one or morepharmaceutically or veterinarily acceptable carriers comprisingexcipients and auxiliaries selected with regard to the intended route ofadministration (e.g., oral, topical or parenteral administration such asinjection) and in accordance with standard practice. In addition, asuitable carrier is selected on the basis of compatibility with the oneor more active ingredients in the composition, including suchconsiderations as stability relative to pH and moisture content.Therefore of note is a composition for protecting an animal from anectoparasitic pest comprising a parasitically effective amount of acompound of the invention and at least one carrier.

Formulations for topical administration are typically in the form of apowder, cream, suspension, spray, emulsion, foam, paste, aerosol,ointment, salve or gel. A topical formulation may be a water-solublesolution, which can be in the form of a concentrate that is dilutedbefore use. Parasiticidal compositions suitable for topicaladministration typically comprise a compound of the present inventionand one or more topically suitable carriers.

In applications of a parasiticidal composition topically to the exteriorof an animal as a line or spot (i.e. “spot-on” treatment), the activeingredient migrates over the surface of the animal to cover most or allof its external surface area. As a result, the treated animal isparticularly protected from invertebrate pests that feed off theepidermis of the animal such as ticks, fleas and lice. Thereforeformulations for topical localized administration often comprise atleast one organic solvent to facilitate transport of the activeingredient over the skin and/or penetration into the epidermis of theanimal. Pour-on or spot-on formulations suitably contain carriers, whichpromote rapid dispersement over the skin surface or in the coat of thehost animal, and are generally regarded as spreading oils. Suitablecarriers are e.g. oily solutions; alcoholic and isopropanolic solutionssuch as solutions of 2-octyldodecanol or oleyl alcohol; solutions inesters of monocarboxylic acids, such as isopropyl myristate, isopropylpalmitate, lauric acid oxalate, oleic acid oleyl ester, oleic acid decylester, hexyl laurate, oleyl oleate, decyl oleate, capric acid esters ofsaturated fat alcohols of chain length C₁₂-C₁₈; solutions of esters ofdicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate,adipic acid diisopropyl ester, di-n-butyl adipate or also solutions ofesters of aliphatic acids, e.g. glycols. It may be advantageous for adispersing agent to be additionally present, such as one known from thepharmaceutical or cosmetic industry. Examples are 2-pyrrolidone,2-(N-alkyl)pyrrolidone, acetone, polyethylene glycol and the ethers andesters thereof, propylene glycol or synthetic triglycerides.

The oily solutions include e.g. vegetable oils such as olive oil,groundnut oil, sesame oil, pine oil, linseed oil or castor oil. Thevegetable oils may also be present in epoxidised form. Paraffins andsilicone oils may also be used.

It may be advantageous for a crystallization inhibitor or a dispersantknown from the pharmaceutical or cosmetic industry also to be present.

A pour-on or spot-on formulation generally contains 1 to 20% by weightof a compound of Formula 1, 0.1 to 50% by weight of dispersing agent and45 to 98.9% by weight of solvent.

The compositions for spot-on application can advantageously comprise:

-   (a) a crystallization inhibitor, in particular one which is present    in a proportion of from 1 to 20% (w/v), preferably from 5 to 15%,    this inhibitor satisfying the test according to which: 0.3 ml of 10%    (w/v) of a compound of Formula 1 in the solvent defined in (c)    below, along with 10% of this inhibitor, are deposited on a glass    slide at 20° C. for 24 hours, after which it is observed with the    naked eye that there are few or no crystals, in particular fewer    than 10 crystals, preferably 0 crystals on the glass slide, (b) an    organic solvent having a dielectric constant of between 10 and 35,    preferably of between 20 and 30, the content of this solvent-   (b) in the overall composition preferably representing the    difference to make the composition up to 100%,-   (c) an organic cosolvent having a boiling point of below 100° C.,    preferably of below 80° C., and having a dielectric constant of    between 10 and 40, preferably of between 20 and 30; this cosolvent    may advantageously be present in the composition in a (c)/b)    weight/weight (w/w) ratio of between 1/15 and 1/2. The solvent is    volatile, so as to serve in particular as a drying promoter, and is    miscible with water and/or with the solvent (b).

A pour-on formulation may also be prepared for control of parasites inan animal of agricultural worth. The pour-on formulations of thisinvention can be in the form of a liquid, powder, emulsion, foam, paste,aerosol, ointment, salve or gel. Typically, the pour-on formulation isliquid. These pour-on formulations can be effectively applied to sheep,cattle, goats, other ruminants, camelids, pigs and horses. The pour-onformulation is typically applied by pouring in one or several lines orin a spot-on the dorsal midline (back) or shoulder of an animal. Moretypically, the formulation is applied by pouring it along the back ofthe animal, following the spine. The formulation can also be applied tothe animal by other conventional methods, including wiping animpregnated material over at least a small area of the animal, orapplying it using a commercially available applicator, by means of asyringe, by spraying or by using a spray race. The pour-on formulationsinclude a carrier and can also include one or more additionalingredients. Examples of suitable additional ingredients are stabilizerssuch as antioxidants, spreading agents, preservatives, adhesionpromoters, active solubilisers such as oleic acid, viscosity modifiers,UV blockers or absorbers, and colourants. Surface active agents,including anionic, cationic, non-ionic and ampholytic surface activeagents, can also be included in these formulations.

The pour-on formulations include a carrier and can also include one ormore additional ingredients. Examples of suitable additional ingredientsare stabilizers such as antioxidants, spreading agents, preservatives,adhesion promoters, active solubilisers such as oleic acid, viscositymodifiers, UV blockers or absorbers, and colourants. Surface activeagents, including anionic, cationic, non-ionic and ampholytic surfaceactive agents, can also be included in these formulations.

The formulations of this invention often include an antioxidant, such asBHT (butylated hydroxytoluene). The antioxidant is generally present inamounts of at 0.005-5% (w/v) a proportion of from 0.005 to 1% (w/v) isoften used, with 0.01 to 0.05% often preferred.

The compositions according to the invention intended for pets, inparticular cats and dogs, are generally applied by being deposited ontothe skin (“spot-on” or “pour-on” application); this is generally alocalized application over a surface area of less than 10 cm²,especially of between 5 and 10 cm2, in particular at two points andpreferably localized between the animal's shoulders. Once deposited, thecomposition diffuses, in particular over the animal's entire body, andthen dries without crystallizing or modifying the appearance (inparticular absence of any whitish deposit or dusty appearance) or thefeel of the fur. The compositions for spot-on application according tothe invention are particularly advantageous owing to their efficacy,their speed of action and the pleasant appearance of the animal's furafter application and drying.

As organic solvent (b) which can be used in the invention, mention maybe made in particular of: acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, dipropylene glycoln-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethylether, ethylene glycol monomethyl ether, monomethylacetamide,dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols,propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone,diethylene glycol monoethyl ether, ethylene glycol and diethylphthalate, or a mixture of at least two of these solvents.

As crystallization inhibitor (a) which can be used in the invention,mention may be made in particular of: polyvinylpyrrolidone, polyvinylalcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethyleneglycols, benzyl alcohol, mannitol, glycerol, sorbitol,polyoxyethylenated sorbitan esters; lecithin, sodiumcarboxymethylcellulose, acrylic derivatives such as methacrylates andthe like, anionic surfactants such as alkaline stearates, in particularsodium, potassium or ammonium stearate; calcium stearate;triethanolamine stearate; sodium abietate; alkyl sulphates, inparticular sodium lauryl sulphate and sodium cetyl sulphate; sodiumdodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, inparticular those derived from coconut oil, cationic surfactants such aswater-soluble quaternary ammonium salts of formula N⁺ R′R″R′″R″″, Y-inwhich the radicals R are optionally hydroxylated hydrocarbon radicalsand Y⁻ is an anion of a strong acid such as the halide, sulphate andsulphonate anions; cetyltrimethylammonium bromide is among the cationicsurfactants which can be used, amine salts of formula N⁺R′R″R′″ in whichthe radicals R are optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is among the cationic surfactants which canbe used, nonionic surfactants such as optionally polyoxyethylenatedsorbitan esters, in particular polysorbate 80, polyoxyethylenated alkylethers; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide, amphoteric surfactants such as substituted laurylcompounds of betaine, or preferably a mixture of at least two of thesecrystallization inhibitors.

In a particularly preferred manner, a crystallization inhibitor couple,namely the combination of a film-forming agent of polymeric type and asurfactant, will be used. These agents will be chosen in particular fromthe compounds mentioned as crystallization inhibitor b).

Among the film-forming agents of polymeric type which are particularlyadvantageous, mention may be made of: the various grades ofpolyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and vinylpyrrolidone.

As regards the surfactants, mention will be made most particularly ofnonionic surfactants, preferably polyoxyethylenated sorbitan esters andin particular the various grades of polysorbate, for example polysorbate80.

The film-forming agent and the surfactant may be incorporated, inparticular, in similar or identical amounts within the limit of thetotal amounts of crystallization inhibitor mentioned elsewhere.

The couple thus produced ensures the objectives of absence ofcrystallization on the hairs and maintenance of the cosmetic appearanceof the coat in a note-worthy manner, that is to say without any tendencytowards stickiness or to a sticky appearance, despite the highconcentration of active material.

As cosolvent (c), mention may be made in particular of: absoluteethanol, isopropanol, methanol.

As antioxidant, standard agents are used in particular, such as:butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate and sodium thiosulphate, or a mixture ofnot more than two of these agents.

The compositions for spot-on application according to the invention areusually prepared by simple mixing of the constituents as definedearlier; advantageously, to begin with, the active material is mixed inthe main solvent and the other ingredients or adjuvants are then added.

The volume applied may be from about 0.3 to 5 ml, preferably about 0.5ml for cats, and from about 0.3 to 3 ml for dogs, according to theweight of the animal.

The composition according to the invention may be in the form of aconcentrated emulsion, suspension or solution for spot-on application toa small area of the animal's skin, generally between the two shoulders(spot-on type solution). In a another aspect of the invention forms ofsolution or suspension to be sprayed, forms of solution, suspension oremulsion to be poured or spread onto the animal (pour-on type solution)an oil, a cream, an ointment or any other fluid formulation for topicaladministration may be provided.

Other delivery systems for relatively hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well-knownexamples of delivery vehicles or carriers for hydrophobic drugs. Inaddition, organic solvents such as dimethylsulfoxide may be used.

The compounds of Formula 1 are generally present in the compositions inconcentrations of 0. 1 to 95 percent by weight, preferably 0.5 to 90percent by weight. Preparations which are intended for directapplication contain the active compound according to the invention inconcentrations of between 0. 001 and 5 percent by weight, preferably0.005 to 3 percent by weight.

Dosages may range from 0.0001 mg/kg of animal body weight to about 1000mg/kg. of the compound of Formula 1. Sometimes dosages may be from 0.1mg/kg of animal body weight to about 200 mg/kg. Often times it would beadvantageous to administer amounts of about 0.01 to about 100 mg orbetween 0.02 to about 50mg/kg. and frequently between 0.1 and 75 mg/kg.Preferably, the treatment is carried out so as to administer to theanimal a dose of from 0.1 to 40 mg/kg and in particular from 1 to 30mg/kg. Administration may be given as a single dose or intermittent intime and may be administered daily, weekly, monthly, bimonthly orquarterly in order to achieve effective results in order to achieveeffective results.

Nevertheless it can at times be necessary to deviate from the amountsmentioned, and in particular to do so in accordance with the body weightof the test animal and/or the method of application, but also because ofthe species of animal and its individual behavior towards themedicament, or the nature of the formulation of the latter and the timeor interval at which it is administered. Thus it can suffice in somecases to manage with less than the above mentioned minimum amount whilein other cases the upper limit mentioned must be exceeded. Wheresubstantial amounts are applied, it can be advisable to divide theseinto several individual administrations over the course of the day. Thegeneral sense of the other statements made above also applies.

For parenteral administration including intravenous, intramuscular andsubcutaneous injection, a compound of the present invention can beformulated in suspension, solution or emulsion in oily or aqueousvehicles, and may contain adjuncts such as suspending, stabilizingand/or dispersing agents. The compounds of the present invention mayalso be formulated for bolus injection or continuous infusion.Pharmaceutical compositions for injection include aqueous solutionspreferably in physiologically compatible buffers containing otherexcipients or auxiliaries as are known in the art of pharmaceuticalformulation. Additionally, suspensions of the active compounds may beprepared in a lipophilic vehicle. Suitable lipophilic vehicles includefatty oils such as sesame oil, synthetic fatty acid esters such as ethyloleate and triglycerides, or materials such as liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers. Alternatively, theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g., sterile, pyrogen-free water, before use.

In addition to the formulations described supra, the compounds of thepresent invention may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly) or by intramuscular orsubcutaneous injection. The compounds of the present invention may beformulated for this route of administration with suitable polymeric orhydrophobic materials (for instance, in an emulsion with apharmacologically acceptable oil), with ion exchange resins, or as asparingly soluble derivative such as, without limitation, a sparinglysoluble salt.

For administration by inhalation, the compounds of the present inventioncan be delivered in the form of an aerosol spray using a pressurizedpack or a nebulizer and a suitable propellant, e.g., without limitation,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane or carbon dioxide. In the case of apressurized aerosol, the dosage unit may be controlled by providing avalve to deliver a metered amount. Capsules and cartridges of, forexample, gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Compounds of the present invention can be delivered by ingestion to theanimal to be protected. After ingestion by the animal to be protected,parasiticidally effective concentrations of compounds of the inventionin the bloodstream protect the treated animal from blood-sucking pestssuch as fleas, ticks and lice. Therefore of note is a composition forprotecting an animal from an invertebrate parasite pest in a form fororal administration (i.e. comprising, in addition to a parasiticidallyeffective amount of a compound of the invention, one or more carriersselected from binders and fillers suitable for oral administration andfeed concentrate carriers).

For oral administration in the form of solutions (the most readilyavailable form for absorption), emulsions, suspensions, pastes, gels,capsules, tablets, boluses, powders, granules, rumen-retention andfeed/water/lick blocks, a compound of the present invention can beformulated with binders/fillers known in the art to be suitable for oraladministration compositions, such as sugars and sugar derivatives (e.g.,lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheatstarch, rice starch, potato starch), cellulose and derivatives (e.g.,methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), proteinderivatives (e.g., zein, gelatin), and synthetic polymers (e.g.,polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g.,magnesium stearate), disintegrating agents (e.g., cross-linkedpolyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can beadded. Pastes and gels often also contain adhesives (e.g., acacia,alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesiumaluminum silicate) to aid in keeping the composition in contact with theoral cavity and not being easily ejected.

If the parasiticidal compositions are in the form of feed concentrates,the carrier is typically selected from high-performance feed, feedcereals or protein concentrates. Such feed concentrate-containingcompositions can, in addition to the parasiticidal active ingredients,comprise additives promoting animal health or growth, improving qualityof meat from animals for slaughter or otherwise useful to animalhusbandry. These additives can include, for example, vitamins,antibiotics, chemotherapeutics, bacteriostats, fungistats, coccidiostatsand hormones.

The compounds of Formula 1 are generally present in the compositions inconcentrations of 0.1 to 95 percent by weight, preferably 0.5 to 90percent by weight. Preparations which are intended for directapplication contain the active compound according to the invention inconcentrations of between 0.001 and 5 percent by weight, preferably0.005 to 3 percent by weight.

Dosages may range from 0.0001 mg/kg of animal body weight to about 1000mg/kg. of the compound of Formula 1. Sometimes dosages may be from 0.1mg/kg of animal body weight to about 200 mg/kg. Often times it would beadvantageous to administer amounts of about 0.01 to about 100 mg orbetween 0.02 to about 50 mg/kg. and frequently between 0.1 and 75 mg/kg.Preferably, the treatment is carried out so as to administer to theanimal a dose of from 0.1 to 40 mg/kg and in particular from 1 to 30mg/kg. Administration may be given as a single dose or intermittent intime and may be administered daily, weekly, monthly, bimonthly orquarterly in order to achieve effective results in order to achieveeffective results.

Nevertheless it can at times be necessary to deviate from the amountsmentioned, and in particular to do so in accordance with the body weightof the test animal and/or the method of application, but also because ofthe species of animal and its individual behavior towards themedicament, or the nature of the formulation of the latter and the timeor interval at which it is administered. Thus it can suffice in somecases to manage with less than the above mentioned minimum amount whilein other cases the upper limit mentioned must be exceeded. Wheresubstantial amounts are applied, it can be advisable to divide theseinto several individual administrations over the course of the day. Thegeneral sense of the other statements made above also applies.

The Compositions of the Invention may Comprise Additional ActiveCompounds:

It is contemplated that additional biologically active compounds may bebe administered at the same time or separately over time to obtainbroader spectrum of parasitic control. Such additional biologicallyactive compounds may be packaged together with the compound of Formula 1as a kit. For convenience sake such additional biologically activecompounds may be formulated into the same composition containing thecompound of Formula 1 and are selected both with respect to theparasites needing control as well as the suitability of the compound inthe mode of administration (oral, parenteral, topical etc.) Thereforethe present invention contemplates the use of compositions characterisedin that they contain, in addition to a compound of Formula 1, furtherauxiliaries and/or active compounds, such as additional biologicallyactive compounds, disinfectants (I the case of topical application) orantibiotics may be admixed to the formulations, or the ready-to-usesolutions, in addition to the customary solid or liquid extenders,diluents and/or surface-active agents.

Of note are additional biologically active compounds or agents selectedfrom art-known anthelmintics, such as, for example, avermectins (e.g.ivermectin, moxidectin, milbemycin), benzimidazoles (e.g. albendazole,triclabendazole), salicylanilides (e.g. closantel, oxyclozanide),substituted phenols (e.g. nitroxynil), pyrimidines (e.g. pyrantel),imidazothiazoles (e.g. levamisole) and praziquantel.

Other biologically active compounds or agents useful in the compositionsof the present invention can be selected from Insect Growth Regulators(IGRs) and Juvenile Hormone Analogues (JHAs) such as diflubenzuron,triflumuron, fluazuron, cyromazine, methoprene, etc., thereby providingboth initial and sustained control of parasites (at all stages of insectdevelopment, including eggs) on the animal subject, as well as withinthe environment of the animal subject.

The compounds of Formula 1 according to the invention may be used aloneor in combination with other biocides. They may be combined withpesticides having the same sphere of activity e.g. to increase activity,or with substances having another sphere of activity e.g. to broaden therange of activity. It can also be sensible to add so-called repellents.If the range of activity is to be extended to endoparasites, e.g.wormers, the compounds of Formula 1 are suitably combined withsubstances having endoparasitic properties. Of course, they can also beused in combination with antibacterial compositions.

Preferred groups of combination partners and especially preferredcombination partners are named in the following, whereby combinationsmay contain one or more of these partners in addition to a compound ofFormula 1.

Suitable partners in the mixture may be biocides, e.g. the insecticidesand acaricides with a varying mechanism of activity, which are named inthe following and have been known to the person skilled in the art for along time, e.g. chitin synthesis inhibitors, growth regulators; activeingredients which act as juvenile hormones; active ingredients which actas adulticides; broad-band insecticides, broad-band acaricides andnematicides; and also the well known anthelminthics and insect- and/oracarid-deterring substances, and also repellents or detachers.

Examples of such biologically active compounds include but are notrestricted to the following: Organophosphates, a class which aregenerally know to be inhibitors of acetyl cholinesterase: acephate,azamethiphos, azinphos-ethyl, azinphos-methyi, bromophos,bromophos-ethyl, cadusafos, chlorethoxyphos, chlorpyrifos,chlorfenvinphos, chlormephos, demeton, demeton-S-methyl,demeton-S-methyl sulphone, dialifos, diazinon, dichlorvos, dicrotophos,dimethoate, disulfoton, ethion, ethoprophos, etrimfos, famphur,fenamiphos, fenitrothion, fensulfothion, fenthion, flupyrazofos,fonofos, formothion, fosthiazate, heptenophos, isazophos, isothioate,isoxathion, malathion, methacriphos, methamidophos, methidathion,methyl-parathion, mevinphos, monocrotophos, naled, omethoate,oxydemeton-methyl, paraoxon, parathion, parathion-methyl, phenthoate,phosalone, phosfolan, phosphocarb, phosmet, phosphamidon, phorate,phoxim, pirimiphos, pirimiphos-methyl, profenofos, propaphos,proetamphos, prothiofos, pyraclofos, pyridapenthion, quinalphos,sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos,thimeton, triazophos, trichlorfon, vamidothion.

Carbamates, a class which are generally known to be inhibitors of acetylcholinesterase: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate,benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb,ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801,isoprocarb, indoxacarb, methiocarb, methomyl, 5methyl-m-cumenylbutyryl(methyl) carbamate, oxamyi, pirimicarb, propoxur,thiodicarb, thiofanox, triazamate, UC-51717 Pyrethroids, a class whichare generally known to be modulators of sodium channels: acrinathin,allethrin, alphametrin, 5-benzyl-3-furylmethyl (E)-(1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate, bifenthrin, 8 cyfluthrin, cyfluthrin,oc-cypermethrin, ,8-cypermethrin, bioallethrin, bioallethrin((S)-Icyclopentylisomer), bioresmethrin, bifenthrin, NCI-85193, cycloprothrin,cyhalothrin, cythithrin, cyphenothrin, deltamethrin, empenthrin,esfenvalerate, ethofenprox, fenfluthrin, fenpropathrin, fenvalerate,flucythrinate, flumethrin, fluvalinate (D isomer), imiprothrin,cyhalothrin, \-cyhalothrin, permethrin, phenothrin, prallethrin,pyrethrins (natural products), resmethrin, tetramethrin, transfluthrin,theta-cypermethrin, silafluofen, T-fluvalinate, tefluthrin,tralomethrin, Zeta-cypermethrin.

Arthropod growth regulators including: a) chitin synthesis inhibitors:benzoylureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron,flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron,triflumuron, buprofezin, diofenolan, hexythiazox, etoxazole,chlorfentazine; b) ecdysone agonists/disruptors: halofenozide,methoxyfenozide, tebufenozide; c) juvenoid hormone mimcs: pyriproxyfen,methoprene, fenoxycarb; d) lipid biosynthesis inhibitors: spirodiclofen.Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118,azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl,bromopropylate, BTG-504, I BTG-505, camphechlor, cartap,chlorobenzilate, chlordimeform, chlorfenapyr, chromafenozide,clothianidine, cyromazine, diacloden, diafenthiuron, DBI-3204, dinactin,dihydroxymethyidihydroxypyrrolidine, dinobuton, dinocap, endosulfan,ethiprole, ethofenprox, fenazaquin, flumite, MTI-800, fenpyroximate,fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox,fluproxyfen, halofenprox, hydramethyinon, IKI-220, kanemite, NC-196,neem guard, nidinorterfuran, nitenpyram, SD-35651, WL-108477, pirydaryl,propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen,NC-1111, R-195, RH-0345, RH-2485, RYI-210, S-1283, S-1833, Sl-8601,silafluofen, silomadine, spinosad, tebufenpyrad, tetradifon,tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad,triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, Yl-5301Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azaconazole,azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeauxmixture, bromuconazole, bupirimate, carpropamid, captafol, captan,carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil,chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil,cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet,diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213,dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine,edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph,fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin,fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole,flutolanil, flutriafol, folpet, fosetyl-aluminium, furalaxyl,furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione,isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam,mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin,metrafenone, myclobutanil, neo-asozin, nicobifen, orysastrobin,oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propamocarb,propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin,pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole,tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram,tiadinil, triadimefon, triadimenol, tricyclazole, trifioxystrobin,triticonazole, validamycin, vinclozin Biological agents: Bacillusthuringiensis ssp alzawai, kurstaki, Bacillus thuringiensis deltaendotoxin, baculovirus, entomopathogenic bacteria, virus and fungiBactericides: chlortetracycline, oxytetracycline, streptomycin,Additional more specific examples of partner insecticides and acaricidesare listed below:

Compound Class Compound Class Abamectin macrocyclic lactones AC 303 630energy production modulator Acephate acetyl cholinesterase inhibitorAcrinathrin sodium channel modulator Alanycarb acetyl cholinesteraseinhibitor Aldicarb acetyl cholinesterase inhibitor alpha.-Cypermethrinsodium channel modulator Alphamethrin sodium channel modulator Amitrazoctopamine receptor ligand Avermectin macrocyclic lactones Azinphos Aacetyl cholinesterase inhibitor Azinphos M acetyl cholinesteraseinhibitor Azinphos-methyl acetyl cholinesterase inhibitor Azocyclotinoxidative phosphorylation inhibitor Bacillus subtil. toxin Bendiocarbacetyl cholinesterase inhibitor Benfuracarb acetyl cholinesteraseinhibitor Bensultap nicotinic acetylcholine agonist/antagonistbeta.-Cyfluthrin sodium channel modulator Bifenthrin sodium channelmodulator Brofenprox sodium channel modulator Bromophos A acetylcholinesterase inhibitor Bufencarb acetyl cholinesterase inhibitorBuprofezin chitin synthesis inhibitor Butocarboxin acetyl cholinesteraseinhibitor Cadusafos acetyl cholinesterase inhibitor Carbaryl acetylcholinesterase inhibitor Carbofuran acetyl cholinesterase inhibitorCarbophenthion acetyl cholinesterase inhibitor Cartap nicotinicacetylcholine agonist/antagonist Chloethocarb acetyl cholinesteraseinhibitor Chlorethoxyfos acetyl cholinesterase inhibitor Chlorfenapyroxidative phosphorylation inhibitor Chlorfluazuron chitin synthesisinhibitor Chlormephos acetyl cholinesterase inhibitor Chlorpyrifosacetyl cholinesterase inhibitor Cis-Resmethrin sodium channel modulatorClofentezine Cyanophos acetyl cholinesterase inhibitor Cycloprothrinsodium channel modulator Cyfluthrin sodium channel modulator Cyhexatinoxidative phosphorylation inhibitor D 2341 (bifenazate) Deltamethrinsodium channel modulator Demeton M acetyl cholinesterase inhibitorDemeton S acetyl cholinesterase inhibitor Demeton-S-methyl acetylcholinesterase inhibitor Dichlofenthion acetyl cholinesterase inhibitorDicliphos acetyl cholinesterase inhibitor Diethion acetyl cholinesteraseinhibitor Diflubenzuron chitin synthesis inhibitor Dimethoate acetylcholinesterase inhibitor Dimethylvinphos acetyl cholinesterase inhibitorDioxathion acetyl cholinesterase inhibitor Doramectin macrocycliclactones DPX-MP062 (indoxacarb) sodium channel modulator Edifenphosacetyl cholinesterase inhibitor Emamectin macrocyclic lactonesEndosulfan gaba-gated chloride channel antagonist Eprinomectinmacrocyclic lactones Esfenvalerate sodium channel modulator Ethiofencarbacetyl cholinesterase inhibitor Ethion acetyl cholinesterase inhibitorEthofenprox sodium channel modulator Ethoprophos acetyl cholinesteraseinhibitor Etrimphos acetyl cholinesterase inhibitor Fenamiphos acetylcholinesterase inhibitor Fenazaquin mitochondrial electron transportinhibitor Fenbutatin oxide oxidative phosphorylation inhibitorFenitrothion acetyl cholinesterase inhibitor Fenobucarb (BPMC) acetylcholinesterase inhibitor Fenothiocarb acetyl cholinesterase inhibitorFenoxycarb juvenile hormone mimic Fenpropathrin sodium channel modulatorFenpyrad mitochondrial electron transport inhibitor Fenpyroximatemitochondrial electron transport inhibitor Fenthion acetylcholinesterase inhibitor Fenvalerate sodium channel modulator Fipronilgaba-gated chloride channel antagonist Fluazinam oxidativephosphorylation uncoupler Fluazuron chitin synthesis inhibitorFlucycloxuron chitin synthesis inhibitor Flucythrinate sodium channelmodulator Flufenoxuron chitin synthesis inhibitor Flufenprox sodiumchannel modulator Fonophos acetyl cholinesterase inhibitor Formothionacetyl cholinesterase inhibitor Fosthiazate acetyl cholinesteraseinhibitor HCH gaba-gated chloride channel antagonist Heptenophos acetylcholinesterase inhibitor Hexaflumuron chitin synthesis inhibitorHexythiazox Hydroprene juvenile hormone mimic Imidacloprid nicotinicacetylcholine agonist/antagonist insect-active fungi insect-activenematodes insect-active viruses Iprobenfos acetyl cholinesteraseinhibitor Isofenphos acetyl cholinesterase inhibitor Isoprocarb acetylcholinesterase inhibitor Isoxathion acetyl cholinesterase inhibitorIvermectin chloride channel activator lambda.-Cyhalothrin sodium channelmodulator Lufenuron chitin synthesis inhibitor Malathion acetylcholinesterase inhibitor Mecarbam acetyl cholinesterase inhibitorMesulfenphos acetyl cholinesterase inhibitor Metaldehyd Methamidophosacetyl cholinesterase inhibitor Methiocarb acetyl cholinesteraseinhibitor Methomyl acetyl cholinesterase inhibitor Methoprene juvenilehormone mimic Metolcarb acetyl cholinesterase inhibitor Mevinphos acetylcholinesterase inhibitor Milbemectin macrocyclic lactones Moxidectinmacrocyclic lactones Naled acetyl cholinesterase inhibitor NI-25,Acetamiprid nicotinic acetylcholine agonist/antagonist Nitenpyramnicotinic acetylcholine agonist/antagonist Nodulisporic acid/derivativesmacrocyclic lactones Omethoat acetyl cholinesterase inhibitor Oxamylacetyl cholinesterase inhibitor Oxydemethon M acetyl cholinesteraseinhibitor Oxydeprofos acetyl cholinesterase inhibitor Parathion acetylcholinesterase inhibitor Parathion-methyl acetyl cholinesteraseinhibitor Permethrin sodium channel modulator Phenthoate acetylcholinesterase inhibitor Phorat acetyl cholinesterase inhibitorPhosalone acetyl cholinesterase inhibitor Phosmet acetyl cholinesteraseinhibitor Phoxim acetyl cholinesterase inhibitor Pirimicarb acetylcholinesterase inhibitor Pirimiphos A acetyl cholinesterase inhibitorPirimiphos M acetyl cholinesterase inhibitor Promecarb acetylcholinesterase inhibitor Propaphos acetyl cholinesterase inhibitorPropoxur acetyl cholinesterase inhibitor Prothiofos acetylcholinesterase inhibitor Prothoat acetyl cholinesterase inhibitorPyrachlophos acetyl cholinesterase inhibitor Pyradaphenthion acetylcholinesterase inhibitor Pyresmethrin sodium channel modulator Pyrethrimsodium channel modulator Pyridaben mitochondrial electron transportinhibitor Pyrimidifen mitochondrial electron transport inhibitorPyriproxyfen juvenile hormone mimic RH 5992 ecdysone agonist RH-2485ecdysone agonist Salithion acetyl cholinesterase inhibitor selamectinmacrocyclic lactones Silafluofen sodium channel modulator Spinosadnicotinic acetylcholine activator Sulfotep acetyl cholinesteraseinhibitor Sulprofos acetyl cholinesterase inhibitor Tebufenozideecdysone agonist Tebufenpyrad mitochondrial electron transport inhibitorTebupirimphos acetyl cholinesterase inhibitor Teflubenzuron chitinsynthesis inhibitor Tefluthrin sodium channel modulator Temephos acetylcholinesterase inhibitor Terbufos acetyl cholinesterase inhibitorTetrachlorvinphos acetyl cholinesterase inhibitor Thiafenox Thiodicarbacetyl cholinesterase inhibitor Thiofanox acetyl cholinesteraseinhibitor Thionazin acetyl cholinesterase inhibitor ThuringiensinTralomethrin sodium channel modulator Triarathen Triazamate acetylcholinesterase inhibitor Triazophos acetyl cholinesterase inhibitorTrichlorfon acetyl cholinesterase inhibitor Triflumuron chitin synthesisinhibitor Trimethacarb acetyl cholinesterase inhibitor Vamidothionacetyl cholinesterase inhibitor XMC (3,5,-Xylyl- acetyl cholinesteraseinhibitor methylcarbamate) Xylylcarb acetyl cholinesterase inhibitor YI5301/5302 zeta.-Cypermethrin sodium channel modulator Zetamethrin sodiumchannel modulator

Non-limitative examples of suitable anthelminthics are named in thefollowing, a few representatives have insecticidal and acaricidalactivity in addition to the anthelminthic activity, and are partlyalready in the above list.

-   (A1)    Praziquantel=2-cyclohexylcarbonyl-4-oxo-1,2,3,6,7,11b-hexahydr-o-4H-pyrazino[2,1-.alpha.]isoquinoline-   (A2)    Closantel=3,5-diiodo-N-[5-chloro-2-methyl-4-(a-cyano-4-chlorob-enzyl)phenyl]-salicylamide-   (A3)    Triclabendazole=5-chloro-6-(2,3-dichlorophenoxy)-2-methylthio-1H-benzimidazole-   (A4)    Levamisol=L-(-)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1b]thiazo-le-   (A5) Mebendazole=(5-benzoyl-1H-benzimidazol-2-yl)carbaminic acid    methylester-   (A6) Omphalotin=a macrocyclic fermentation product of the fungus    Omphalotus olearius described In WO 97/20857-   (A7) Abamectin=avermectin B1-   (A8) Ivermectin=22,23-dihydroavermectin B1-   (A9)    Moxidectin=5-O-demethyl-28-deoxy-25-(1,3-dimethyl-1-butenyl)-6-,28-epoxy-23-(methoxyimino)-milbemycin    B-   (A10)    Doramectin=25-cyclohexyl-5-O-demethyl-25-de(1-methylpropyl)-a-vermectin    A1a-   (A11) Milbemectin=mixture of milbemycin A3 and milbemycin A4-   (A12) Milbemycinoxim=5-oxime of milbemectin

Non-limitative Examples of Suitable Repellents and Detachers are:

-   (R1) DEET (N,N-diethyl-m-toluamide)-   (R2) KBR 3023 N-butyl-2-oxycarbonyl-(2-hydroxy)-piperidine-   (R3)    Cymiazole=N,-2,3-dihydro-3-methyl-1,3-thiazol-2-ylidene-2,4-xy-lidene

The aforementioned partners in the mixture are best known to specialistsin this field. Most are described in various editions of the PesticideManual, The British Crop Protection Council, London, and others in thevarious editions of The Merck Index, Merck & Co., Inc., Rahway, N.J.,USA or in patent literature. Therefore, the following listing isrestricted to a few places where they may be found by way of example.

-   (I) 2-Methyl-2-(methylthio)propionaldehyde-O-methylcarbamoyloxime    (Aldicarb), from The Pesticide Manual, 11.sup.th Ed. (1997), The    British Crop Protection Council, London, page 26;-   (II)    S-(3,4-dihydro-4-oxobenzo[d]-[1,2,3]-triazin-3-ylmethyl)O,O-di-methyl-phosphorodithioate    (Azinphos-methyl), from The Pesticide Manual, 11.sup.thEd. (1997),    The British Crop Protection Council, London, page 67;-   (III)    Ethyl-N-[2,3-dihydro-2,2-dimethylbenzofuran-7-yloxycarbonyl-(-methyl)aminothio]-N-isopropyl-.beta.-alaninate    (Benfuracarb), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 96;-   (IV)    2-Methylbiphenyl-3-ylmethyl-(Z)-(1RS)-cis-3-(2-chloro-3,3,3-tr-ifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate    (Bifenthrin), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 118;-   (V) 2-tert-butylimino-3-isopropyl-5-phenyl-1,3,5-thiadiazian-4-one    (Buprofezin), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 157;-   (VI) 2,3-Dihydro-2,2-dimethylbenzofuran-7-yl-methylcarbamate    (Carbofuran), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 186;-   (VII)    2,3-Dihydro-2,2-dimethylbenzofuran-7-yl-(dibutylaminothio)met-hylcarbamate    (Carbosulfan), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 188;-   (VIII) S,S′-(2-dimethylaminotrimethylene)-bis(thiocarbamate)    (Cartap), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 193;-   (IX)    1-[3,5-Dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phe-nyl]-3-(2,6-difluorobenzoyl)-urea    (Chlorfluazuron), from The Pesticide Manual, 11.sup.thEd. (1997),    The British Crop Protection Council, London, page 213;-   (X) O,O-diethyl-O-3,5,6-trichloro-2-pyridyl-phosphorothioate    (Chlorpyrifos), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 235;-   (XI) (RS)-.alpha.-cyano-4-fluoro-3-phenoxybenzyl-(1RS,3RS;    1RS,3RS)-3-(2,2-dichlorovinyl)-2,2-di-methylcyclopropanecarboxylate    (Cyfluthrin), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 293;-   (XII) Mixture of    (S)-.alpha.-cyano-3-phenoxybenzyl-(Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate    and    (R)-.alpha.-cyano-3-phenoxybenzyl-(Z)-(1R,3)-3-(2-chloro-3,3,3-trifluorop-ropenyl)-2,2-dimethylcyclopropanecarboxylate    (Lambda-Cyhalothrin), from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 300;-   (XIII) Racemate consisting of    (S)-.alpha.-cyano-3-phenoxybenzyl-(2)-(1R,3R)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate    and    (R)-.alpha.-cyano-3-phenoxybenzyl-(1S,3S)-3-(2,2-dichlorovinyl)-2,2-dimet-hylcyclopropanecarboxylate    (Alpha-cypermethrin), from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 308;-   (XIV) a mixture of the stereoisomers of    (S)-.alpha.-cyano-3-phenoxy-benzyl    (1RS,3RS,1RS,3RS)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropaneca-rboxylate    (zeta-Cypermethrin), from The Pesticide Manual, 11.sup.thEd. (1997),    The British Crop Protection Council, London, page 314;-   (XV)    (S)-.alpha.-cyano-3-phenoxybenzyl-(1R,3R)-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate    (Deltamethrin), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 344;-   (XVI) (4-chlorophenyl)-3-(2,6-difluorobenzoyl)urea (Diflubenzuron),    from The Pesticide Manual, 11.sup.thEd. (1997), The British Crop    Protection Council, London, page 395;-   (XVII)    (1,4,5,6,7,7-Hexachloro-8,9,10-trinorborn-5-en-2,3-ylenebism-ethylene)-sulphite    (Endosulfan), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 459;-   (XVIII) .alpha.-ethylthio-o-tolyl-methylcarbamate (Ethiofencarb),    from The Pesticide Manual, 11.sup.thEd. (1997), The British Crop    Protection Council, London, page 479;-   (XIX) O,O-dimethyl-O-4-nitro-m-tolyl-phosphorothioate    (Fenitrothion), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 514;-   (XX) 2-sec-butylphenyl-methylcarbamate (Fenobucarb), from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 516;-   (XXI)    (RS)-.alpha.-cyano-3-phenoxybenzyl-(RS)-2-(4-chlorophenyl)-3-methylbutyrate    (Fenvalerate), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 539;-   (XXII)    S-[formyl(methyl)carbamoylmethyl]-O,O-dimethyl-phosphorodith-ioate    (Formothion), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 625;-   (XXIII) 4-Methylthio-3,5-xylyl-methylcarbamate (Methiocarb), from    The Pesticide Manual, 11.sup.thEd. (1997), The British Crop    Protection Council, London, page 813;-   (XXIV) 7-Chlorobicyclo[3.2.0]hepta-2,6-dien-6-yl-dimethylphosphate    (Heptenophos), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 670;-   (XXV)    1-(6-chloro-3-pyridylmethyl)-N-nitroimidazolidin-2-ylidenamin-e    (Imidacloprid), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 706;-   (XXVI) 2-isopropylphenyl-methylcarbamate (Isoprocarb), from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 729;-   (XXVII) O,S-dimethyl-phosphoramidothioate (Methamidophos), from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 808;-   (XXVIII) S-Methyl-N-(methylcarbamoyloxy)thioacetimidate (Methomyl),    from The Pesticide Manual, 11.sup.thEd. (1997), The British Crop    Protection Council, London, page 815;-   (XXIX) Methyl-3-(dimethoxyphosphinoyloxy)but-2-enoate (Mevinphos),    from The Pesticide Manual, 11.sup.thEd. (1997), The British Crop    Protection Council, London, page 844;-   (XXX) O,O-diethyl-O-4-nitrophenyl-phosphorothioate (Parathion), from    The Pesticide Manual, 11.sup.thEd. (1997), The British Crop    Protection Council, London, page 926;-   (XXXI) O,O-dimethyl-O-4-nitrophenyl-phosphorothioate    (Parathion-methyl), from The Pesticide Manual, 11.sup.thEd. (1997),    The British Crop Protection Council, London, page 928;-   (XXXII)    S-6-chloro-2,3-dihydro-2-oxo-1,3-benzoxazol-3-ylmethyl-O,O-diethyl-phosphordithioate    (Phosalone), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 963;-   (XXXIII)    2-Dimethylamino-5,6-dimethylpyrimidin-4-yl-dimethylcarbama-te    (Pirimicarb), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 985;-   (XXXIV) 2-isopropoxyphenyl-methylcarbamate (Propoxur), from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 1036;-   (XXXV)    1-(3,5-dichloro-2,4-difluorophenyl)-3-(2,6-difluorobenzoyl)u-rea    (Teflubenzuron), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1158;-   (XXXVI) S-tert-butylthiomethyl-O,O-dimethyl-phosphorodithioate    (Terbufos), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1165;-   (XXXVII)    ethyl-(3-tert.-butyl-1-dimethylcarbamoyl-1H-1,2,4-triazol-5-yl-thio)-acetate,    (Triazamate), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1224;-   (XXXVIII) Abamectin, from The Pesticide Manual, 11.sup.thEd. (1997),    The British Crop Protection Council, London, page 3;-   (XXXIX) 2-sec-butylphenyl-methylcarbamate (Fenobucarb), from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 516;-   (XL) N-tert.-butyl-N′-(4-ethylbenzoyl)-3,5-dimethylbenzohydrazide    (Tebufenozide), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1147;-   (XLI)    (.±.)-5-amino-1-(2,6-dichloro-.alpha.,.alpha.,.alpha.-triflu-oro-p-tolyl)-4-trifluoromethyl-sulphinylpyrazol-3-carbonitrile    (Fipronil), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 545;-   (XLII) (RS)-.alpha.-cyano-4-fluoro-3-phenoxybenzyl(1RS ,3RS; 1 RS    ,3RS)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate    (beta-Cyfluthrin), from The Pesticide Manual, 11.sup.thEd. (1997),    The British Crop Protection Council, London, page 295;-   (XLIII)    (4-ethoxyphenyl)-[3-(4-fluoro-3-phenoxyphenyl)propyl](dimet-hyl)silane    (Silafluofen), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1105;-   (XLIV) tert.-butyl    (E)-.alpha.-(1,3-dimethyl-5-phenoxypyrazol-4-yl-methylenamino-oxy)-p-toluate    (Fenpyroximate), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 530;-   (XLV)    2-tert.-butyl-5-(4-tert.-butylbenzylthio)-4-chloropyridazin-3-(2H)-one    (Pyridaben), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1161;-   (XLVI) 4-[ [4-(1,1-dimethylphenyl)phenyl]ethoxy]-quinazoline    (Fenazaquin), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 507;-   (XLVII) 4-phenoxyphenyl-(RS)-2-(pyridyloxy)propyl-ether    (Pyriproxyfen), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1073;-   (XLVIII)    5-chloro-N-{2-[4-(2-ethoxyethyl)-2,3-dimethylphenoxy]ethyl-}-6-ethylpyrimidine-4-amine    (Pyrimidifen), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1070;-   (XLIX)    (E)-N-(6-chloro-3-pyridylmethyl)-N-ethyl-N′-methyl-2-nitrovi-nylidenediamine    (Nitenpyram), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 880;-   (L)    (E)-N.sup.1-[(6-chloro-3-pyridyl)methyl]-N.sup.2-cyano-N.sup.1-methylacetamidine    (NI-25, Acetamiprid), from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 9;-   (LI) Avermectin B.sub.1, from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 3;-   (LII) an insect-active extract from a plant, especially    (2R,6aS,12aS)-1,2,6,6a,12,12a-hexhydro-2-isopropenyl-8,9-dimethoxy-chrome-no[3,4-b]furo[2,3-h]chromen-6-one    (Rotenone), from The Pesticide Manual, 11.sup.thEd. (1997), The    British Crop Protection Council, London, page 1097; and an extract    from Azadirachta indica, especially azadirachtin, from The Pesticide    Manual, 11.sup.thEd. (1997), The British Crop Protection Council,    London, page 59; and-   (LII) a preparation which contains insect-active nematodes,    preferably Heterorhabditis bactedophora and Heterorhabditis megidis,    from The Pesticide Manual, 11.sup.thEd. (1997), The British Crop    Protection Council, London, page 671; Steinemema feltiae, from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 1115 and Steinemema scaptedsci, from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 1116;-   (LIV) a preparation obtainable from Bacillus subtilis, from The    Pesticide Manual, 11.sup.thEd. (1997), The British Crop Protection    Council, London, page 72; or from a strain of Bacillus thuringiensis    with the exception of compounds isolated from GC91 or from    NCTC11821; The Pesticide Manual, 11.sup.thEd. (1997), The British    Crop Protection Council, London, page 73;-   (LV) a preparation which contains insect-active fungi, preferably    Verticillium lecanii, from The Pesticide Manual, 11.sup.th Ed.    (1997), The British Crop Protection Council, London, page 1266;    Beauveda brogniartii, from The Pesticide Manual, I 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 85 and    Beauveda bassiana, from The Pesticide Manual, 11.sup.thEd. (1997),    The British Crop Protection Council, London, page 83;-   (LVI) a preparation which contains insect-active viruses, preferably    Neodipridon Sertifer NPV, from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 1342;    Mamestra brassicae NPV, from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 759 and    Cydia pomonella granulosis virus, from The Pesticide Manual,    11.sup.thEd. (1997), The British Crop Protection Council, London,    page 291;-   (CLXXXI)    7-chloro-2,3,4a,5-tetrahydro-2-[methoxycarbonyl(4-trifluor-omethoxyphenyl)-carbamoyl]indol[1,2e]oxazoline-4a-carboxylate    (DPX-MP062, Indoxycarb), from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 453;-   (CLXXXII)    N′-tert.-butyl-N′-(3,5-dimethylbenzoyl)-3-methoxy-2-methy-lbenzohydrazide    (RH-2485, Methoxyfenozide), from The Pesticide Manual, 11.sup.thEd.    (1997), The British Crop Protection Council, London, page 1094; and-   (CLXXXIII) (N′-[4-methoxy-biphenyl-3-yl]-hydrazinecarboxylic acid    isopropylester (D 2341), from Brighton Crop Protection Conference,    1996, 487-493; (R2) Book of Abstracts, 212th ACS National Meeting    Orlando, Fla., Aug. 25-29 (1996), AGRO-020. Publisher: American    Chemical Society, Washington, D.C. CONEN: 63BFAF.

As a rule, the anthelminthic compositions according to the inventioncontain 0.1 to 99% by weight, especially 0.1 to 95% by weight of activeingredient of Formula 1 mixtures thereof, 99.9 to 1% by weight,especially 99.8 to 5% by weight of a solid or liquid admixture,including 0 to 25% by weight, especially 0.1 to 25% by weight of asurfactant.

As noted above, in another embodiment of the process according to theinvention, compounds of Formula 1 and the additional compounds notedhereinbefore may be applied in a distinct and separate manner over time.

The following TESTS demonstrate the control efficacy of compounds ofthis invention on specific pests. The pest control protection affordedby the compounds is not limited, however, to these species.

BIOLOGICAL EXAMPLES OF THE INVENTION Test A

Adult H. irritans exigua Feeding Assay

A blood meal assay was used to determine the LC₅₀ for test compound(3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide)on adult H.irritans exigua. Six (6) serial dilutions of the testcompound were prepared in decoagulated bovine blood that was storedrefrigerated. Ivermectin was included as a positive control compound anda negative control was included in each assay. Flies were collected witha net immediately before each assay from yarded commercial cattle. About100 adults were introduced into a mesh cage (30×30×30 cm) containing onecotton gauze (4×4×1 cm) soaked in one blood/insecticide concentration.There were 3 replicate cages of each blood/insecticide concentration.Blood gauzes were replaced every 12 hours. The untreated control cagesreceived untreated decoagulated blood. All cages were labelled andstored for 72 hours at 25-27° C. in the dark at ambient relativehumidity (70-85%). Every 12 hours the numbers of dead flies were countedin each cage. At 72-96 hours all flies were counted and percentagemortality was calculated. Data was subjected to log-probit analysis todetermine the LC₅₀ if there is a dose response in the assay.

Adult H. irritans exigua feeding assay % Adult mortality Exposure timeCompound Concentration 7 hr 17 hr 24 hr Test compound 600 ppb 80.5 94.796.5 400 ppb 78.8 89.8 94.9 200 ppb 77.3 78.8 80.3 Ivermectin 600 ppb86.0 95.5 100.0 400 ppb 80.1 94.2 98.0 200 ppb 78.5 91.8 93.1 ControlMortality 10.8 16.8 21.0

Test B

Adult A. aegypti Contact Assay

Adult A.aegypti were exposed to six rates of the positive controlcompound permethrin and the experimental compounds diluted with acetone.The dilutions of test compound(3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide)used were 0 ppm (acetone only), 0.1 ppm, 1 ppm, 10 ppm, 20 ppm, 50 ppm,100 ppm, 500 ppm and 1000 ppm. Each rate was replicated 5 times. Thetest was conducted in 100 mL conical flasks. The entire inside of theflasks was coated with Coatasil the day before the treatments areapplied. A 0.5 ml aliquot of each rate was applied to the bases only ofthe flasks. At 24 hours after the surfaces had been treated adultA.aegypti were anaesthetised using food grade carbon dioxide and 10mosquitoes were introduced to each conical flask and the mouths of theflasks covered with parafilm. Small holes were made in the parafilm toallow gas exchange. The bioassay was run for 8 hrs at 25±2° C. andrelative humidity of approximately 70%.

Mosquito adults A. aegypti contact assay Compound LC50 (ug/flask) LC90(ug/flask) Test compound 0.025 0.033 Permethrin 0.025 0.046 Untreatedcontrol mortality - 6%

Test C

In vivo evaluation Against Artificial Infestations With Cat Fleas (C.felis) and Brown Dog Ticks (R. sanguineus) on Dogs

Twenty five dogs were used in this study that investigated the efficacyof test compound(3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide)against fleas and ticks. Two groups (one treated and one untreated) offive dogs were used to evaluate the flea efficacy whilst two groups offive dogs (one treated and one untreated) were used to investigate thetick efficacy. The dogs in the respective groups were infested weeklywith 40 unfed adult ticks and 100 cat fleas. One group was treated withADVANTIX and served as a positive control. The dogs in this group wereinfested simultaneously with fleas and ticks. Test compound wasformulated in NMP. The treatment was applied topically via syringe onthe dorsal line of the animals as a line-on at 60 mg/kg dose rate. Theefficacy of the compound was assessed by weekly tick and flea counts.The weekly counts generated in the treated groups were compared to thepositive and negative untreated control (UTC) group counts to evaluateefficacy of Test compound.

In vivo Evaluation Against Artificial Infestations With C. felis and R.sanguineus on Dogs

Flea efficacy (%) compared to the untreated control Group Treatment Day2 Day 9 Day 16 Day 23 Day 29 4 Test 99.6 99.7 99.7 98.7 97.3 compound 5ADVANTIX 100 100 89.0 76.7 69.1 UTC Vehicle 57.0 73.8 78.2 76.4 73.2(Mean # (NMP) of fleas)

Tick efficacy (%) compared to the untreated control Group Treatment Day2 Day 9 Day 16 Day 23 Day 29 3 Test 74.0 94.9 95.0 90.6 86.2 compound 5ADVANTIX 44.0 99.3 89.7 84.2 79.7 UTC Vehicle 10.0 27.6 25.2 27.8 24.6(Mean # (NMP) of ticks)Small numbers of engorged ticks were found on dogs in both theexperimental and positive control treatment groups at all assessmenttimes. Test compound provided a similar level of protection againstticks to that of the positive control product ADVANTIX, with slightlylower numbers of live ticks collected from the dogs during all but oneassessment over the 30 day period. At 48 hours after treatment, the testcompound achieved 74% efficacy compared to the negative control. Thisresult was 30% higher than the ADVANTIX that gave 44% efficacy. Testcompound provided over 94.9%, 90.5% and 90.6% efficacy at 9, 16 and 23days post-treatment which was a level of control similar to the ADVANTIXwith 99.3%, 89.7% and 84.2% respectively. The test compound continued toprovide a high level of protection at 30 days post treatment, with 86.2%efficacy compared to 79.7% provided by the ADVANTIX.

Overall, the test compound treatment was more effective against fleasthan the positive control product, with over 99.5% efficacy during thefirst three assessments at 2, 9 and 16 days post-treatment and 97.3%efficacy at 30 days post-treatment. Although the ADVANTIX achieved 100%efficacy during the first 9 days after application, this dropped tobelow 90% by day 16 and below 70% by day 30.

Test D

In vivo Evaluation Against Artificial Infestations With Cat Fleas (C.felis) on Mice

For evaluating control of the cat flea (Ctenocephalides felis Bouche), aCD-1® mouse (about 30 g, male, obtained from Charles River Laboratories,Wilmington, Mass.) was orally dosed with test compound in an amount of10 mg/kg solubilized in propylene glycol/glycerol formal (60:40). Twohours after oral administration of the test compound, approximately 8 to16 adult fleas were applied to each mouse. The fleas were then evaluatedfor mortality 48 hours after flea application to the mouse.3-bromo-1-(3-chloro-2-pyridinyl)-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamidecaused 45% mortality.

Although the present invention and its advantages have been described indetail, it should be understood that various changes, substitutions andalterations can be made herein without departing from the spirit andscope of the invention as defined by the appended claims.

1. A method of controlling or preventing infestation of a hematophagousectoparasitic insect on a homeothermic animal by administering to theanimal a composition comprising a parasiticidally effective amount of3-bromo-N-[4-cyano-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamideor an N-oxide or pharmaceutically or veterinarily acceptable saltthereof.
 2. The method of claim 1 wherein the hematophagousectoparasitic insect is selected from the group consisting of fleas,ticks, lice mites, and biting flies.
 3. The method of claim 1 whereinthe administering is oral.
 4. The method of claim 1 wherein theadministering is parenteral.
 5. The method of claim 1 wherein theadministering is topical.
 6. The method of claim 1 wherein the animal isa cat or dog.
 7. The method of claim 1 wherein the animal is a herdanimal.
 8. The method of any of claims 1-7 wherein the compositioncomprises at least one additional component selected from the groupconsisting of solvents and/or carriers, emulsifiers and/or dispersingagents.
 9. The method of claim 8 wherein the composition comprises atleast one additional biologically active compound or agent.
 10. Themethod of claim 9 wherein the additional biologically active compound oragent is selected from the group consisting of macrocyclic lactones,acetyl cholinesterase inhibitors, arthropod growth regulators,GABA-gated chloride channel antagonists, mitochondrial electrontransport inhibitors, nicotinic acetylcholineagonists/antagonists/activator, oxidative phosphorylation inhibitors,anthelminthics, sodium channel modulators or other antiparasiticcompounds.
 11. The method of claim 10 wherein said biologically activecompound is a macrocyclic lactone.
 12. The method of claim 10 whereinsaid biologically active compound is an acetyl cholinesterase inhibitorselected from the group of organophosphates and carbamates.
 13. Themethod of claim 10 wherein said biologically active compound is anarthropod growth regulator selected from the group of chitin synthesisinhibitors, ecdysone agonists/disruptors, lipid biosynthesis inhibitorand juvenile hormone mimics.
 14. The method of claim 10 wherein saidbiologically active compound is a GABA-gated chloride channelantagonist.
 15. The method of claim 10 wherein said biologically activecompound is a mitochondrial electron transport inhibitor.
 16. The methodof claim 10 wherein said biologically active compound is a nicotinicacetylcholine agonist/antagonist/activator.
 17. The method of claim 10wherein said biologically active compound is an oxidativephosphorylation inhibitor.
 18. The method of claim 10 wherein saidbiologically active compound is an anthelminthic.
 19. The method ofclaim 10 wherein said biologically active compound is a sodium channelmodulator.